*The Department of Neurology, Colentina Clinical Hospital has the approval of the local Research Ethics Committee for implementing the GENDYS clinical study.

Project leader: Bogdan Ovidiu Popescu, Professor of Neurology and Head of the Neurology Teaching Department at the Colentina Clinical Hospital (Senior Neurologist / Consultant, Research Professor)

Status of the project: ongoing (end date: the 31st of December 2019)

Status of the clinical study: ongoing and still recruiting persons with isolated focal dystonia until the 28th of December 2018 (110 persons with focal isolated dystonia have already been enrolled); the written informed consent of the participant is mandatory for study enrollment.

Budget: 850.000,00 lei

Research team:

Bogdan Ovidiu Popescu (Professor of Neurology and Head of the Neurology Teaching Department at the Colentina Clinical Hospital, UMFCD; Research Professor; Senior Neurologist / Consultant)

Focal dystonia refers to the sustained or intermittent involuntary contractions of one or several muscles resulting in abnormal postures (e.g., blepharospasm, torticolis). Though this group of diseases is relatively rare, dystonia is the third most common movement disorder after Parkinson’s Disease and essential tremor. In many cases there are no accompanying symptoms, thus the name focal isolated dystonia; no structural lesions are found in the muscles or nervous system, and the affected persons are otherwise healthy while the pathogeny remains mostly occult, therefore this type of dystonia is classified as primary or idiopathic. Similar to other movement disorders, dystonia may result in high disability and decreased quality of life. Currently, no curative or highly effective symptomatic treatments are available. Considering the above a better understanding of this group of diseases in highly welcomed.

Scientific rationale for the study:

Isolated focal dystonia is the most common movement disorder after Parkinson disease and essential tremor. Is relatively rare, but may be highly debilitating. No preventive or disease modifying treatments are available. Symptomatic treatments are only modestly effective in most of the cases. The typical onset is in adulthood. The etiology is genetic in some cases, but over 75% are idiopathic. Next Generation Whole Exome Sequencing (WES) has been successfully used in the recent years for finding rare disease-causing alleles. Compared with more traditional approaches this method successfully identified several dystonia-related genes. The GENDYS project uses WES for identifying potential new gene variants related to dystonia.

ABSTRACT OF THE PROJECT:

Isolated focal dystonia is the most common movement disorder after Parkinson disease and essential tremor. Is relatively rare, but may be highly debilitating. No preventive or disease modifying treatments are available. Symptomatic treatments are only modestly effective. The typical onset is in adulthood. The etiology is genetic in some cases, but over 75% are idiopathic. Whole-exome sequencing (WES) has been successfully used in the recent years for finding rare disease-causing alleles. Compared with more traditional approaches this method successfully identified several dystonia-related genes. Our project proposes to identify relevant genomic profiles by WES, replicate previously published results and test the usefulness of targeted next-generation sequencing as a sensitive and accurate tool for the simultaneous screening of dystonia. Our objectives will be reached in two steps by: 1) screening a well described homogenous group of Romanian dystonia cases (n=120, i.e. moderate size) and controls (n=97) using our own designed targeted sequencing panel of previously isolated dystonia-associated genes (DYTs) and 2) identifying of new gene/variants related to the disease by analyzing the negative-known DYTs subjects using a high-throughput sequencing approach. The potential gene interactions will be evaluated by logistic regression analyses. For multiple comparisons the Bonferroni correction will be used. We consider genomic profiling of the affected individuals and identification of new disease-related gene to be a research priority in the field of dystonia, paving the way for future therapeutic studies and putatively serving for the development of preventive strategies in those at risk. Moreover, this study brings novel contribution to the international state of the art by genetically characterizing adult-onset isolated focal dystonia on unrelated affected subjects using the whole-exome sequencing.

OBJECTIVES OF THE PROJECT:

To describe potential correlations between genetic variants and the clinical profile in a group of Romanian patients with adult-onset focal isolated dystonia, by targeted sequencing the currently known adult-onset focal isolated dystonia-related genes.

To identify potentially new genetic variants related to adult-onset focal isolated dystonia, by evaluating the sub-group of patients negative for currently known focal isolated dystonia-related gene variants, using a Next Generation whole-exome sequencing approach.

Two doctoral fellows were recruited: Iulia Popescu-Olaru (first year PhD student; thesis on the relation between certain genetic variants and the response to symptomatic therapy in focal-onset idiopathic dystonia) and Ovidiu-Lucian Băjenaru (first year PhDstudent; thesis on the genetics of focal-onset idiopathic dystonia).

Research status, scientific communications and publications

The first round of genetic tests using our customized panel (80 focal isolated dystonia patients) and the interim analysis of the clinical data from the first 90 patients have been performed. A review paper relevant for the research will be submitted for publication in the near future. Interim results of the research will be submitted for presentation at the 2019 edition of the EAN Congress.